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Article Dans Une Revue PLoS Pathogens Année : 2020

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

Béatrice Cambien
Kevin Lebrigand
Laure-Emmanuelle Zaragosi
Frédéric Bost
Roger Rezzonico
Robert Barthel
  • Fonction : Auteur
Georges Vassaux

Résumé

Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumor-types for which human and canine pathologies are closely related at the molecular level. The efficacy of an oncolytic vaccinia virus (VV) was compared in low-passage primary carcinoma cells from TNBC versus non-TNBC. Non-TNBC cells were 28 fold more sensitive to VV than TNBC cells in which VV replication is impaired. Single-cell RNA-seq performed on two different TNBC cell samples, infected or not with VV, highlighted three distinct populations: naïve cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptomes of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bioin-formatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrated experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, our data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrates that single-cell transcriptomics can be used to identify cellular factors influencing viral replication.
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Dates et versions

hal-02992299 , version 1 (07-11-2020)

Identifiants

Citer

Béatrice Cambien, Kevin Lebrigand, Alberto Baeri, Nicolas Nottet, Catherine Compin, et al.. Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics. PLoS Pathogens, 2020, 16 (10), pp.e1008660. ⟨10.1371/journal.ppat.1008660⟩. ⟨hal-02992299⟩
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